Combined therapy with PJ34, a poly(ADP-ribose)polymerase inhibitor, reduces tissue plasminogen activator-induced hemorrhagic transformations in cerebral ischemia in mice
Combined therapy with PJ34, a poly(ADP-ribose)polymerase inhibitor, reduces tissue plasminogen activator-induced hemorrhagic transformations in cerebral ischemia in mice
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DOI：
10.1111/j.1472-8206.2012.01036.x
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发表时间：
2013-08-01
影响因子：
2.9
通讯作者：
Margaill, Isabelle
中科院分区：
文献类型：
--
作者：
Haddad, Marianne;Beray-Berthat, Virginie;Margaill, Isabelle
重组组织型纤溶酶原激活剂（rt-PA）是目前唯一批准用于缺血性卒中患者溶栓的药物治疗。虽然缺血组织的再灌注是必不可少的，但rt-PA的使用由于其狭窄的治疗窗口和出血性转化的风险而受到限制。最近的研究表明，rt-PA放大了缺血后核酶聚（ADP-核糖）聚合酶（PARP）的激活。这种酶已被证明有助于血脑屏障的破坏和缺血后自发性出血转化。因此，我们研究了PJ 34（N-（6-氧代-5，6-二氢菲啶-2-基）-2-（N，N-二甲基氨基）乙酰胺盐酸盐）（PARP的有效抑制剂）减少永久性局灶性脑缺血小鼠rt-PA后发生的出血性转化的能力。通过左大脑中动脉的管腔内闭塞产生缺血，并用载体rt-PA（10 mg/kg，静脉内，6小时）或rt-PA + PJ 34（3、6或12 mg/kg，i. p.，缺血开始时和4小时后）。缺血发作后48小时评价出血转化、神经系统检查和梗死体积。rt-PA延迟给药导致出血性转化增加，并加重神经功能缺损。给予PJ 34（3 mg/kg）显著减少出血性转化，这种效果不是由于基质金属蛋白酶活性的改变。此外，PJ 34还改善了rt-PA治疗的缺血小鼠的神经功能。总之，PARP抑制剂PJ 34使rt-PA在实验性缺血性卒中中更安全。
Recombinant tissue-type plasminogen activator (rt-PA) is presently the only pharmacological treatment approved for thrombolysis in patients suffering from ischemic stroke. Although reperfusion of ischemic tissue is essential, the use of rt-PA is limited due to its narrow therapeutic window and risk of hemorrhagic transformations. Recent studies have shown that rt-PA amplifies the post-ischemic activation of the nuclear enzyme poly(ADP-ribose)polymerase (PARP). This enzyme has been shown to contribute to both the breakdown of the blood brain barrier and spontaneous hemorrhagic transformations after ischemia. We therefore examined the capacity of PJ34 (N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-2-(N,N-dimethylamino) acetamide hydrochloride), a potent inhibitor of PARP, to reduce the hemorrhagic transformations that occur after rt-PA in mice with permanent focal cerebral ischemia. Ischemia was produced by intraluminal occlusion of the left middle cerebral artery and treated with vehicle, rt-PA (10mg/kg, i.v., 6h after occlusion) or rt-PA plus PJ34 (3, 6 or 12mg/kg, i.p., at ischemia onset and 4h later). Hemorrhagic transformations, neurological examination, and infarct volumes were evaluated 48h after the onset of ischemia. Delayed administration of rt-PA resulted in increased hemorrhagic transformations and aggravated the neurological deficit. Giving PJ34 (3mg/kg) markedly reduced the hemorrhagic transformations, an effect not owing to a modification of matrix metalloprotease activity. Furthermore, PJ34 improved the neurological functions of rt-PA-treated ischemic mice. To conclude, the PARP inhibitor PJ34 makes rt-PA safer in experimental ischemic stroke.